KATP channels are integral to the functions of many different types of cells and tissues. However, even though they were first described almost 25 years ago, the physiological and pathophysiological roles of these channels are only now emerging for most tissues. Electrophysiological and pharmacological methods have allowed for a good understanding of the roles of KATP channels. The molecular identification of KATP channels (Kir6.1, Kir6.2, SUR1, SUR2A and/or SUR2B subunits) has further advanced our knowledge regarding the distribution and function of these channels. The overriding hypothesis to be examined is that physiological and pathophysiological events are subject to the activity of KATP channels that are present in multiple tissues and that synchronous interaction between channel activities in diverse tissue types determines the nature of the physiological or pathophysiological outcome. Conventional pharmacological methods cannot be used to examine this hypothesis in a complex biological setting since these compounds lack required specificity for different classes of KATP channels present in diverse tissue types. Conventional knockout mouse models have been developed for each of the KATP channel subunits and the availability of these animal models has added significantly to our knowledge of the functions of KATP channels in the in-vivo setting. However, since the expression is eliminated in all somatic cells the use of these animals provides challenges when defining the roles of KATP channel subunits in complex biological settings (such as ischemia/reperfusion). To examine the interplay of KATP channels present in multiple tissues and their synchronous interaction in diverse tissue types, new tools are needed in which KATP channels are eliminated only in specific tissues, cell types or subcellular compartments. The purpose of this proposal is therefore to generate four mouse models of conditional knockouts of each of the KATP channel subunits. Given the rich diversity of KATP channels (both in terms to their tissue distribution and molecular composition), a dire need exists to generate conditional knockout mice devoid of each of the KATP channel subunits. The development of these animal models will have a wide ranging impact, not only on our own research, but also on the field in general since these animals generated as part of these studies will allow investigators working in diverse areas (cardiology, endocrinology, neurology, etc) to unravel the tissue specific functions of KATP channel in health and disease. PUBLIC HEALTH RELEVANCE: ATP-sensitive K+ channels are unique in that they transduce intracellular energy metabolism to cellular activity and excitability and they have very important roles on the functions of many different cell types and they help to maintain blood glucose levels, regulate blood flow, participate in the secretion of neurotransmitters and protect against ischemic insults. New challenges have arisen in the study of KATP channel in physiological and pathophysiological context that cannot be addressed using existing tools (even with the available conventional knockout mice), which is the rationale for our proposal to generate new genetically altered mouse models in which KATP channel subunits can be deleted specifically in certain tissue types. These mice, which will be widely shared with the scientific community, will undoubtedly lead to significant breakthroughs in the study of KATP channels in many study areas (in addition to our own research) and this will have a major impact on the fields of biomedical, behavioral and clinical research.